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<p>Epidermal growth factor receptor (<i>EGFR</i>) exon 20 insertions are the third most common <i>EGFR</i> mutation subtype in non-small cell lung cancer, occurring in up to ~4% of cases. Although the clinical profile overlaps with classical sensitizing <i>EGFR</i> mutations, most exon 20 insertions confer primary resistance to earlier generation epidermal growth factor receptor tyrosine kinase inhibitors, reflecting position- and variant-dependent steric constraints within the adenosine triphosphate–binding pocket. More than 100 distinct variants have been described, motivating structure- and variant-informed frameworks for diagnosis and treatment selection. Accurate detection is therefore essential: fixed-content polymerase chain reaction assays may miss clinically actionable variants, whereas next-generation sequencing improves variant capture and supports standardized reporting, including identification of co-alterations. Plasma cell-free DNA testing can complement tissue profiling when biopsy is not feasible, but low circulating tumour DNA shedding can yield false-negative results, supporting reflex tissue testing after negative plasma findings when clinical suspicion remains high. Therapeutically, the landscape has shifted rapidly since 2021, with the introduction of exon 20 insertion–directed strategies including bispecific antibodies and next-generation tyrosine kinase inhibitors, alongside an expanding pipeline of mutant-selective agents and rational combinations. Despite these advances, response durability remains limited for many patients, and both intrinsic and acquired resistance via on-target changes, bypass signalling and tumour evolution continues to drive unmet need. Future progress will likely depend on central nervous system–active strategies, adaptive sequencing guided by longitudinal molecular profiling and combination approaches that address pathway bypass and tumour heterogeneity.</p>

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EGFR Exon 20 Insertion–Mutated Non-Small Cell Lung Cancer: Current Treatment Landscape and Future Directions

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月19日

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  • Eunice L. Y. Lau,
  • Noor Rashidha Binte Meera Sahib,
  • Carina Ysha P. Cangco,
  • Aaron C. Tan

摘要

Epidermal growth factor receptor (EGFR) exon 20 insertions are the third most common EGFR mutation subtype in non-small cell lung cancer, occurring in up to ~4% of cases. Although the clinical profile overlaps with classical sensitizing EGFR mutations, most exon 20 insertions confer primary resistance to earlier generation epidermal growth factor receptor tyrosine kinase inhibitors, reflecting position- and variant-dependent steric constraints within the adenosine triphosphate–binding pocket. More than 100 distinct variants have been described, motivating structure- and variant-informed frameworks for diagnosis and treatment selection. Accurate detection is therefore essential: fixed-content polymerase chain reaction assays may miss clinically actionable variants, whereas next-generation sequencing improves variant capture and supports standardized reporting, including identification of co-alterations. Plasma cell-free DNA testing can complement tissue profiling when biopsy is not feasible, but low circulating tumour DNA shedding can yield false-negative results, supporting reflex tissue testing after negative plasma findings when clinical suspicion remains high. Therapeutically, the landscape has shifted rapidly since 2021, with the introduction of exon 20 insertion–directed strategies including bispecific antibodies and next-generation tyrosine kinase inhibitors, alongside an expanding pipeline of mutant-selective agents and rational combinations. Despite these advances, response durability remains limited for many patients, and both intrinsic and acquired resistance via on-target changes, bypass signalling and tumour evolution continues to drive unmet need. Future progress will likely depend on central nervous system–active strategies, adaptive sequencing guided by longitudinal molecular profiling and combination approaches that address pathway bypass and tumour heterogeneity.